The invention relates to a process for the preparation of 2(S),4(S),5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amides and their physiologically acceptable salts; and the new compounds used as intermediates in the multistage process.
In EP-A-0 678 503, xcex4-amino-xcex3-hydroxy-xcfx89-aryl-alkanecarbox-amides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
It has now been surprisingly found that these alkane-carboxamides can be prepared both in high total yields and in a high degree of purity, and that selectively pure diastereomers are obtainable, if the double bond of 2,7-dialkyl-8-aryl-4-octenic acid or 2,7-dialkyl-8-aryl-4-octenic acid ester is simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the halolactone is converted to a hydroxylactone and then the hydroxy group is converted to a leaving group, the leaving group substituted with azide, the lactone amidated and then the azide converted to the amine group. Apart from the high yields and stereoselectivities in the individual process steps, particular attention is drawn to the fact that substantially fewer by-products are formed in the azidation step.
A primary object of the invention is a process for the preparation of compounds of formula I, 
wherein
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, and R5 is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6-alkyl, C1-C6alkanoyloxy-C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylamino-C1-C6-alkyl, C1-C6-dialkylamino-C1-C6-alkyl, C1-C6-alkanoylamido-C1-C6-alkyl, HO(O)Cxe2x80x94C1-C6-alkyl, C1-C6alkyl-Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, C1-C6alkyl-HNxe2x80x94C(O)xe2x80x94C1-C6alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6-alkyl, comprising
a) the reaction of a compound of formula II, 
with an amine of formula R5xe2x80x94NH2 to form a compound of formula III, 
and
b) reduction of the azide group of the compound of formula III to the amine group and isolation of the compounds of formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of compounds of formula II by reacting
c1) a compound of formula IV, 
wherein R6 is C1-C20alkyl, C3-C12cycloalkyl, C3-C12cycloalkyl-C1-C6alkyl, C6-C10aryl or C6-C10-aryl-C1-C6alkyl, with a halogenation agent to form a compound of formula VI, or
c2) a carboxylic acid of formula V, or a salt of this carboxylic acid, 
with a halogenation agent to form a compound of formula VI, 
wherein X is Cl, Br or I,
d) reaction of the compound of formula VI in the presence of an alkali metal or alkaline earth metal hydroxide or an alcohol to form a compound of formula VII, 
wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group,
e) hydrolysis of the compound of formula VII in the presence of an acid to form a compound of formula VIII, 
f) substitution of the hydrogen atom of the hydroxyl group in the compound of formula VIII and conversion thereof to a leaving group AO to form compounds of formula IX, 
g) and then reaction of the compound of formula IX with an azidation agent to form a compound of formula II, or
h) reaction if the compound of formula VIII directly with a zinc azide/-bis-pyridine complex in the presence of a tertiary phosphine and an azodicarboxylate, if necessary in an organic solvent, to form a compound of formula II.
As an alkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
As a halogenalkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
As an alkoxy, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
As an alkoxyalkyl, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
As a C1-C6alkoxy-C1-C6alkyloxy, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyoxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R1 is methoxy- or ethoxy-C1-C4alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula I, wherein R1 is 1-methoxyprop-3-yloxy and R2 is methoxy.
As an alkyl, R3 and R4 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula I are in each case isopropyl.
As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise 1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl are preferred.
As a C1-C6hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or 4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.
As a C1-C6alkoxy-C1-C6alkyl, R5 may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl, 2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl, 2-ethoxyethy-1-yl, 2-ethoxyprop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or 4-ethoxybut-1-yl.
As a C1-C6alkanoyloxy-C1-C6alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxy-ethyl, propionyloxyethyl and butyroyloxyethyl.
As a C1-C6aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or 3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.
As C1-C6alkylamino-C1-C6alkyl and C1-C6dialkylamino-C1-C6-alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C1-C4alkyl groups and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylaminoeth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl, 3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and 4-dimethylaminobut-1-yl.
As a C1-C6alkanoylamido-C1-C6alkyl, R5 may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl, 2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and 4-butyroylamidoeth-1-yl.
As a HO(O)Cxe2x80x94C1-C6alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.
As a C1-C6alkyl-Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl, 4-methoxycarbonylbut-1-yl, ethoxycarbonylmethyl, 2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl-prop-1-yl, and 4-ethoxycarbonylbut-1-yl.
As a H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl, 2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl, 3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl, 3-carbamido-3-ethylprop-1-yl, 3-carbamido-2,2-dimethylprop-1-yl, 2-, 3-, 4- or 5-carbamidopent-1-yl, 4-carbamido-3,3- or -2,2-dimethylbut-1-yl.
As a C1-C6alkyl-HNxe2x80x94C(O)xe2x80x94C1-C6-alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.
A preferred subgroup of compounds of formula I is that in which R1 is C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyloxy, R2 is C1-C4alkoxy, R3 is C1-C4alkyl, R4 is C1-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl which if necessary is N-monosubstituted or N-di-C1-C4alkyl substituted.
A more preferred subgroup of compounds of formula I is that in which R1 is methoxy-C2-C4-alkyloxy, R2 is methoxy or ethoxy, R3 is C2-C4alkyl, R4 is C2-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl.
An especially preferred compound of formula I is that in which R1 is 3-methoxy-prop-3-yloxy, R2 is methoxy, R3 and R4 are 1-methyleth-1-yl, and R5 is H2NC(O)xe2x80x94[C(CH3)2]xe2x80x94CH2xe2x80x94.
As an alkyl, R6 may be linear or branched and comprise preferably 1 to 12 C atoms, 1 to 8 C atoms being especially preferred. R6 is particularly preferred as a linear C1-C4alkyl. Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl. Especially preferred are methyl and ethyl.
As a cycloalkyl, R6 may preferably comprise 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclododecyl.
As a cycloalkyl-alkyl, R6 may comprise preferably 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1 to 4 C atoms in the alkyl group, 1 or 2 C atoms being especially preferred. Some examples are cyclopropyl methyl, cyclobutyl methyl, cyclopentyl methyl or cyclopentyl ethyl, and cyclohexyl methyl or cyclohexyl ethyl.
As an aryl, R6 is preferably phenyl or naphthyl.
As an aralkyl, R6 is preferably benzyl or phenyl ethyl.
In formula VII, M may be an alkaline earth metal, for example Mg, Ca or Sr. Equivalent in the context of the invention means the charge equalization of cation and anion. M is preferably an alkali metal, for example Li, Na or K. Particular preference is for M as Li. If M is the residue of an alcohol minus a hydroxyl group, it may be the R6 group, including the embodiments and preferences described hereinbefore, in particular alkyl and cycloalkyl.
Residue A in the leaving group AO is preferably the residue of an organic acid, for example C1-C8acyl, particular preference being for C1-C8sulfonyl. The acyl residue may be a carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid and benzoic acid substituted if necessary with C1-C4alkyl, C1-C4alkoxy or halogen. The sulfonyl residue A may correspond for example to formula R7xe2x80x94SO2xe2x80x94, wherein R7 is C1-C8alkyl, C1-C8halogenalkyl, C3-C8cycloalkyl, or phenyl or benzyl either unsubstituted or substituted with C1-C4alkyl, C1-C4alkoxy, C1-C4hakogenalkyl or halogen. Some examples of sulfonyl residues are methyl, ethyl, phenyl, methylphenyl, dimethyl phenyl, trimethyl phenyl, trifluoromethyl phenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl and trifluoromethyl sulfonyl.
The individual process steps may be carried out in the presence of solvent. Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).
Process Step a)
The reaction of compounds of formula II to form compounds of formula III with a compound R5NH2 by opening of the lactone ring can be carried out with or without solvent. The reaction is expediently carried out in the presence of alcohols or amines, which can form activated carbonic esters or carboxamides. Such compounds are well-known. These may be 2-hydroxypyridine, N-hydroxycarboxamides and imides, and carboximides (N-hydroxysuccinimide). Organic solvents are used as solvent, tertiary amines being of advantage, for example trimethylamine or triethylamine. The reaction temperature may range for example from approximately 40xc2x0 C. to 150xc2x0 C. and preferably from 50xc2x0 C. to 120xc2x0 C.
Process Step b)
Reduction of the azide group to the amine group in the compounds of formula III takes place in a manner known per se (see Chemical Reviews, Vol. 88 (1988), pages 298 to 317), for example using metal hydrides or more expediently using a catalytic method with hydrogen in the presence of homogeneous (Wilkinson catalyst) or heterogeneous catalysts, for example Raney nickel or precious metal catalysts such as platinum or palladium, if necessary on substrates such as carbon. The hydrogenation can also be carried out if necessary catalytically under phase transfer conditions, for example with ammonium formate as hydrogen donor. It is of advantage to use organic solvents. The reaction temperature may range for example from approximately 0xc2x0 C. to 200xc2x0 C. and preferably from 10xc2x0 C. to 100xc2x0 C. Hydrogenation may be carried out at normal pressure or increased pressure up to 100 bar, for example, and preferably up to 50 bar.
The compounds of formula I may be converted to addition salts in a manner known per se by treatment with monobasic or polybasic, inorganic or organic acids. Hemifumarates are preferred.
Process Step c1)
Suitable chlorination, bromination and iodination agents are elemental bromine and iodine, in particular N-chlorine, N-bromine and N-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides and sulfonimides, for example chloramine T. The reaction is advantageously carried out in organic solvents miscible with water, such as tetrahydrofuran or dioxane in the presence of at least an equivalent volume of water. The reaction takes place first at low temperatures, for example xe2x88x9220 to 10xc2x0 C., and then at elevated temperatures, for example 30 to 100xc2x0 C. The presence of inorganic or organic acids may be advantageous. Suitable acids are for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, H2SO4, H3PO4, hydrogen halides, acid ion exchange resins, and acids immobilized on solid carriers. The halolactone may be isolated for example by extraction with organic solvents.
Process Step c2)
Suitable chlorination, bromination and iodination agents are elemental bromine and iodine, in particular N-chloro, N-bromo and N-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides and sulfonimides, for example chloramine T. The reaction is advantageously carried out in organic solvents, such as halogenated hydrocarbons (chloroform, dichloromethane). The reaction temperature may range for example from approximately xe2x88x9270xc2x0 C. to ambient temperature and preferably from xe2x88x9230xc2x0 C. to 10xc2x0 C. The halolactone may be isolated for example by extraction with organic solvents.
Suitable salts of carboxylic acids of formula V are for example alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as ammonium salts. The ammonium salts may derive from ammonia, primary, secondary or tertiary amines, or they may be quaternary ammonium salts. The amines may be acyclic or cyclic and comprise heteroatoms from the C and S group. The amines may comprise 1 to 18 C atoms, 1 to 12 being preferred and 1 to 8 especially preferred. Quaternary ammonium salts may comprise 4 to 18 C atoms, 4 to 12 being preferred and 4 to 8 especially preferred. Some examples of amines are methylamine, dimethylamine, triethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, Tripropylamine, isopropylamine, butylamine, dibutylamine, tributylamine, phenylamine, methylethylamine, methyldiethylamine, phenylmethylamine, benzylamine, cyclopentylamine, cyclohexylamine, piperidine, N-methyl-piperidine, morpholine, pyrrolidine, and 2-phenylethylamine. Salt formation allows a more efficient purification of the carboxylic acids of formula V with regard to their optical and chemical purity, especially when crystalline salts are formed with the selection of amines. The salts may be converted before the reaction to the carboxylic acids of formula V. However, the salts may also be used directly for halolactonization. In this case, the addition of acids, for example trifluoroacetic acid or other strong acids, is recommended, as described under process step c1).
The halolactonization is surprisingly stereoselective, and the desired cis-halolactones are formed in yields of up to 90% or more.
Process Step d)
The reaction of a compound of formula VI with at least equimolar quantities of alkali or alkaline earth metal hydroxides is expediently carried out in a polar organic solvent, for example alcohols such as isopropanol, and at low temperatures of, for example, xe2x88x9220 to 30xc2x0 C. Aqueous solutions of hydroxides are preferably used, lithium hydroxide being especially preferred. The compound of formula VII does not need to be isolated, but the reaction mixture can be used directly in process step e). The desired stereoisomer is also formed in this step at high yields of up to 90% or more.
The reaction of a compound of formula VI with at least equimolar quantities of an alcohol, especially a C1-C8alkanol and in particular methanol or ethanol, is expediently carried out in a polar organic solvent, for example ethers or the alkanols used for esterification, and at low temperatures of, for example xe2x88x9220 to 30xc2x0 C. Bases are preferably used as well, for example alkali metal hydrogencarbonates or alkali metal carbonates, potassium hydrogencarbonate being especially preferred. The compound of formula VII does not need to be isolated, but the reaction mixture can be used directly in process step e). The desired stereoisomer is also formed in this reaction at high yields of up to 90% or more.
Process Step e)
Lactonization of the compounds of formula VII to form compounds of formula VIII is expediently carried out at a temperature of xe2x88x9220 to 50xc2x0 C. and in the presence of a preferably polar solvent, such as an alcohol (isopropanol) or ether (tetrahydrofuran, dioxane). It is advantageous to use inorganic acids, especially mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid. The hydroxylactone of formula VII may be isolated for example by extraction with organic solvents. The desired stereoisomer is also formed in this step at high yields of up to 90% or more.
Process Step f)
Conversion of the hydroxy group to a leaving group may be carried out in organic solvents, preferably polar organic solvents, and at temperatures of xe2x88x9220 to 50xc2x0 C. Acid halogenides, such as acid chlorides and acid bromides, are preferably used as reagents. Sulfonyl chlorides or bromides are especially preferred. The reaction is advantageously carried out in the presence of equivalent quantities of a base for bonding of the acid. Suitable bases are in particular tertiary amines, such as trimethylamine or triethylamine and dimethylaminopyridine. The hydroxylactone of a compound of formula VII may be isolated for example by extraction with organic solvents. The yields are up to 90% or more.
Process Step g)
Suitable azidation agents are for example metal azides, especially alkaline earth metal azides and alkali metal azides, as well as silyl azides. Especially preferred azidation agents are lithium azide, sodium azide and potassium azide. The reaction may be carried out in organic solvents, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethylformamide (DMF), 1,3-dimethylimidazolidinone (DMI), toluene or methylcyclohexane. The reaction temperature may range for example from approximately 20xc2x0 C. to 150xc2x0 C. and preferably from 50xc2x0 C. to 120xc2x0 C. It may be expedient to include the use of phase transfer catalysts. The preparation and synthetic use of azides are described for example by E. F. V. Scriven in Chemical Reviews, Vol. 88 (1988), pages 298 to 317 The yield amounts to an outstanding 70% or more.
In one variant, the introduction of the leaving group in process step f) and the azidation in process step g) may be carried out simultaneously in one reaction vessel.
Process Step h)
In one variant, the azidation may also be carried out directly with the hydroxyl compound of formula VIII. This reaction has been described by David. L. Hughes in Organic Preparations and Procedures Int. (1996), 28 (2), pp. 127-164 and by M. C. Viaud et al. in Synthesis (1990), pp. 130 to 131. The azidation is carried out with at least equimolar quantities of zinc azide/bis-pyridine in the presence of, for example, triphenylphosphine in quantities of 2 equivalents or more, and approximately equal quantities of an azodicarboxylate such as azodiisopropylcarboxylate. The reaction is carried out in an organic solvent, especially an aromatic hydrocarbon, such as benzene, toluene or xylene. The reaction temperature may be xe2x88x9220 to 80xc2x0 C.
Some intermediates prepared using the process according to the invention are new and represent further objects of the invention.
A further object of the invention is thus a compound of formula X, 
wherein
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, and R5 is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6-alkyl, C1-C5alkanoyloxy-C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylamino-C1-C6-alkyl, C1-C6-dialkylamino-C1-C6-alkyl, C1-C6-alkanoyl-.
An object of the invention in a broader sense is a compound of formula VII, 
wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group, and
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C3-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, and R4 is C1-C6alkyl.
For residues R1, R2, R3, and R4, as well as for M, in compounds of formula VII, the embodiments and preferences described hereinbefore apply.
An object of the invention is a compound of formula XIII 
wherein R11 is an alkali metal, an equivalent alkaline earth metal, hydrogen or the residue of an alcohol minus a hydroxyl group, and
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, and R4 is C1-C6alkyl,
For residues R1, R2, R3, R4, and R11 in compounds of formula XIII, the embodiments and preferences described hereinbefore apply.
The carboxylic acids of formula V used in process step c) may be prepared in a manner known per se by hydrolysis of hydrolysable acid derivatives such as carbonic esters, carbooxamides or carboxylates. The hydrolysis may be carried out with acids or bases. Hydrolysis with a base is preferred, for example with alkali metal hydroxides (LiOH, KOH and NaOH), which can be added as aqueous solution or as a solid. The reaction is advantageously carried out in water, organic solvents (alcohols and ethers) or mixtures thereof. The reaction temperature may range up to the boiling temperature of the solvent used. After removal of the solvent, the residue of the reaction is expediently taken up with an aqueous acid, such as hydrochloric acid, and the compound of formula V is extracted (for example with ethers) and purified. The hydrolysis is quantitative, and the pure compound of formula V is obtained in yields of more than 90%. It is possible to carry out the hydrolysis at the same time as the halolactonization in one reaction vessel. The hydrolysis may also be carried out enzymatically.
The compounds of formula XIII are obtainable by reacting a compound of formula XIV 
with a compound of formula XV, 
wherein R1 to R4, and R11 are as defined hereinbefore, including the preferences, Y is Cl, Br or I, and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably Br and especially Cl.
The coupling of Grignard reagents with alkenyl halogenides in an ether such as tetrahydrofuran or dioxane as solvents in the presence of catalytic quantities of a soluble metal salt or metal complex, for example an iron, nickel or palladium salt or an iron, nickel or palladium complex (such as iron trichloride, iron acetonyl acetate iron benzoyl acetonate, nickel acetonyl acetate, and iron, nickel or palladium complexes with tertiary phosphines or ditertiary diphosphines such as triphenylphosphine, tricyclohexylphosphine, 1,2-diphenylphosphinoethane, 1,2-diphenylphosphinopropane, 1,2-diphenylphosphinofuran, and 1,2-diphenylphosphinobutane is known. Examples of metal complexes and metal complex salts are dichloronickel(1,2-diphenylphosphinoethane) and dichloropalladium(1,2-diphenylphosphinoethane). The presence of an additive stabilizing the metal salts or metal complexes and metal complex salts can be of advantage. Examples are DMPU, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-morpholine, amines such as triethylamine and tetramethylethylenediamine, as well as mixtures of at least two of these additives. When using iron acetonylacetate, the addition of a mixture of DMPU and tetramethylethylendiamine has proved successful. When using dichloronickel(1,2-diphenylphosphinoethane), the addition of triethylamine has proved to be of advantage.
The reaction is described by G. Cahiez et al. in Synthesis (1998), pp. 1199-1200. The reaction temperature may for example be xe2x88x9250 to 80xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. Catalytic quantities may for example be 0.1 to 20% by weight in relation to a compound of formula XIV. It is expedient to carry out the reaction so that initially a compound of formula XIV is converted to a Grignard compound (for example with magnesium) and then adding a solution of a compound of formula XV, metal salt, metal complex, or metal complex salt and the stabilizing additive, or vice versa.
It may be of advantage if only catalytic quantities of an additive stabilizing the metal complexes, for example triethylamine or DMPU, are used. Catalytic quantities may for example be 0.1 to 10 mol percent, preferably 1 to 5 mol percent, in relation to compounds of formula XIV or XV.
Compounds of formula XIV in the form of their racemates or enantiomers are known or capable of being prepared according to analogous processes. For example, RIR2phenylaldehyde may be reacted with R3diethoxyphosphorylacetic acid ester to form 2-R3-3-(R1R2phenyl)acrylic acid esters, these may then be hydrogenated to form the corresponding propionic acid esters, the ester group saponified and the carboxylic acid reduced to alcohol, and finally the hydroxyl group substituted with halogen. Enantiomers are obtainable by separating the racemates of the carboxylic acids with for example quinine or by enzymatic resolution of the racemates of the corresponding carbonic esters. Details are described in the examples. A possible asymmetric synthesis of compounds of formula XIV is described in EP-A-0 678 503.
The compounds of formula XV are obtainable by reacting for example carbonic esters or derivatives of formula R4CH2COOR11 with 1,3-dihalogenpropene in the presence of strong amine bases such as alkali metal amides (Li-N(i-propyl)2 or lithium hexamethyldisilazane) to form compounds of formula XV, or by preparing through derivatization in a manner known per se carboxylic acids, carboxylic acid halogenides, carboxamides and carboxylic acid salts from e.g. the carbonic esters of formula XV. The desired enantiomers can be obtained from the racemates in a manner known per se by separating the racemates, for example by crystallization from addition salts of carboxylic acids using optically active bases. It is more advantageous to separate the racemates by treating esters of formula XV with esterases.
With the choice of carbonic esters and carboxylic acids of formulae IV and V, the compounds of formula I, which per se are complex compounds, can be prepared in a convergent and simple manner, which is especially true for this enantioselective or diastereoselective synthesis. The total yield from all process steps a) to h) may amount to 40% or more, which makes industrial application feasible.
The following examples explain the invention in more detail.
A) Preparation of Compounds of Formula IV